Dipetidyl peptidase-IV (DPP-IV) is a serine protease that recognizes and cuts a sequence with proline, hydroxyproline or alanine at the 2nd position from the N-terminal thereof (H-Xaa-Pro, H-Xaa-Hyp or H-Xaa-Ala, in which Xaa indicates an amino acid). It is known that DPP-IV is broadly distributed in humans, not only in tissues of the kidneys, liver, and salivary glands, but also in body fluids such as serum, urine, and saliva. Though its physiological role has not been completely clarified as yet, DPP-IV may participate in regulating biological functions as it cuts various physiologically-active peptides(non-patent reference 1). In particular, it is now specifically noticed that DPP-IV may control the activity of a hormone, incretin that participates in inhibiting blood glucose increase.
Incretin is a hormone that is secreted from the intestines after nutrient ingestion in humans, and it acts on pancreatic β-cells to enhance insulin secretion, thereby regulating the blood glucose level. It is known that the incretin activity is attenuated in type 2 diabetics (non-patent reference 2), and it is considered that the activity attenuation will be one reason for the expression of diabetes. Accordingly, it is expected that the postprandial hyperglycemia of diabetics could be ameliorated.
At present, glucagon-like peptide (hereinafter referred to as “GLP-1”) is known as a compound that exhibits a most effective incretin activity in humans. GLP-1 is, after secreted in blood, immediately inactivated, and it is known that the inactivation is essentially owing to the action of DPP-IV that cleaves it (non-patent reference 3). Further, the inactive GLP-1 cleaved by DPP-IV binds to a GLP-1 receptor and prevents active GLP-1 from binding to the receptor. Accordingly, it is believed that the incretin action of GLP-1 is thereby attenuated (non-patent reference 4).
For these reasons, it is believed that a DPP-IV inhibitor may prevent the inactivation of GLP-1, therefore enhancing the incretin action of active GLP-1, and, as a result, it may prevent the postprandial hyperglycemia of diabetics. In addition, since incretin enhances the glucose-dependent insulin secretion in humans, it is expected that the DPP-IV inhibitor may be a safe remedy without side effect such as hypoglycemia which is often seen in use of existing insulin-secretion remedies.
On the other hand, some 2-cyanopyrrolidine derivatives are known, having a DPP-IV inhibiting activity (patent references 1 to 7).
Of those, International Publication WO02/30890 pamphlet (patent reference 5) specifically discloses compounds of a general formula (A), saying that the compounds will be effective for prevention and remedy of diabetes and for prevention and remedy of other diseases that are induced or exacerbated by impaired glucose tolerance, hyperinsulinemia and diabetic complications.
(In the formula, the symbols are as defined in the patent document.)
On the other hand, International Publication WO02/38541 pamphlet (patent reference 6) discloses compounds of a general formula (B), saying that the compounds significantly inhibit the blood glucose level increase in an oral glucose tolerance test with Zucker Fatty rats.
(In the formula, the symbols are as defined in the patent document.)
International Publication WO03/002553 pamphlet (patent reference 7) discloses compounds of general formulae (C), (D), (E), (F), (G) and (H), saying that the compounds are useful for treating disorders such as diabetes, obesity.
(In the formula, the symbols are as defined in the patent document.)
Given that situation, it is greatly desired to develop drugs that have more excellent DPP-IV inhibiting activity.
Non-patent reference 1: Mentlein R., Regulatory Peptide, 1999, Vol. 85, pp. 9-24.
Non-patent reference 2; Nauck M. A., Diabetologia, 1986, Vol. 29, pp. 46-52.
Non-patent reference 3; Drucker D. J., Diabetes, 1998, Vol. 47, pp. 159-169
Non-patent reference 4: Knudsen L. B., European Journal of Pharmacology, 1996, Vol. 318, pp. 429-435.
Patent reference 1: International Publication WO98/19998 pamphlet.
Patent reference 2: International Publication WO01/96295 pamphlet.
Patent reference 3: International Publication WO00/34241 pamphlet.
Patent reference 4: International Publication WO01/55105 pamphlet.
Patent reference 5: International Publication WO02/30890 pamphlet.
Patent reference 6: International Publication WO02/38541 pamphlet.
Patent reference 7: International Publication WO03/002553 pamphlet.